Certain aminoalkyl phenylcarbamates are selective acetylcholine esterase inhibitors and are therefore potentially useful as pharmaceuticals for the treatment of brain disorders such as dementia, Alzheimer's Disease, Huntington's Chorea, tardive dyskinesias, confusion disorders and ataxia. One such compound, the (2R,3R)-hydrogen tartrate salt of (S)-ethylmethylcarbamic acid 3-[1-(dimethylamino)ethyl]phenyl ester (Rivastigmine hydrogen tartrate, 2), is marketed as a pharmaceutical for the treatment of dementia of the Alzheimer's type.

Processes for the preparation of these types of aminoalkyl phenylcarbamates are described in patents U.S. Pat. No. 4,948,807, EP 193926, U.S. Pat. No. 5,602,176, GB 2409453, CN 1486973, WO 2004/037771, WO 2007/026373, WO 2007/025481 and WO 2007/014973. The patents disclose the preparation of phenyl carbamate compounds involving reaction of phenol compounds with appropriate isocyanates or carbamoyl halides. The process using isocyanates involves the use of benzene as a solvent. Isocyanates such as lower alkyl isocyanates are hazardous to handle due to their toxic and volatile nature.
The other reported alternative is the use of carbamoyl halides along with reactive bases like sodium hydride, to prepare the carbamates. The carbamoyl halides are carcinogenic substances and are not easy to handle on industrial scale. In addition, the use of a reactive base like sodium hydride on an industrial scale is hazardous and operationally non-user friendly due to its pyrophoric and reactive nature.
PCT application WO 03/101917 discloses a process for the preparation of the title phenyl carbamate compounds involving reaction of phenol compounds with an alkylamine-4-nitrophenyl carbamate. The invention partially overcomes the deficiency posted by the use of isocyanates or carbamoyl halides reported in the prior art. However, the reaction requires harsh conditions and long reaction time. For example, in Example 3 of the application, the reaction of 3-(1-dimethylaminoethyl)phenol and N-ethyl-N-methyl-4-nitrophenyl carbamate was carried out in dimethylsulfoxide (DMSO) in the presence of anhydrous potassium carbonate at 90-100° C. for 35-40 hours. In addition, the reaction condition may not be suitable for the reaction of chiral intermediate such as (S)-3-(1-dimethylaminoethyl)phenol since the stereochemistry at the chiral center may be racemized when heated with a base for an extended period of time.
Crystalline forms of Rivastigmine hydrogen tartrate have been disclosed in the prior art, for example, U.S. Pat. No. 5,602,176 and WO 2007/026373. The characteristics affected by polymorphism include solubility, dissolution rate, stability, hygroscopicity and solid-state reactivity. The effect of polymorphism on bioavailability is the most important consequence if the bioavailability is mediated via dissolution. The amorphous form of Rivastigmine hydrogen tartrate has not been reported.
It is therefore an object of the invention to provide a more industrially applicable process for the preparation of aminoalkyl phenyl carbamate compounds.
It is a further object of the invention to use less toxic substances in the formation of racemic and enantiomerically-enriched (R)- or (S)-Rivastigmine, and their pharmaceutically-acceptable addition salts.
It is yet a further object of the invention to provide an amorphous form of Rivastigmine such as Rivastigmine hydrogen tartrate.
Further and other objects of the invention will become apparent to those skilled in the art when considering the following summary of the invention and the more detailed description of the embodiments of the invention described herein.